4-Substituted 2-iminoimidazolidine compounds

ABSTRACT

This invention provides a novel class of 2-iminoimidazolidines which include 4-substituted derivatives such as 4-(2-chloroethyl)-1-methyl-2-methylimino-3-phenyl imidazolidine fumarate: ##STR1## This illustrated 4-substituted 2-iminoimidazolidine compound exhibits cardiovascular hypotensive, hypoglycemic (glucose tolerance, and sugar cataract) and anti-inflammatory (pleural effusion) pharmacological activities in test animals.

BACKGROUND OF THE INVENTION

There are a number of organic compounds listed in the chemicalliterature which contain a 2-iminoimidazolidine nucleus: ##STR2##

Among the known compounds are1-[p-(2-aminoethyl)-phenylsulfonyl]-3-butyl-4-ethyl-2-iminoimidazolidineand 1-cyclohexyl-2-imino-4-methyl-3-(p-tolylsulfonyl)imidazolidine.

Another known 2-iminoimidazolidine compound is enduracididine, anaminoacid which is derived from enduracidin by acid hydrolysis (J.Antibiot. (Tokyo), 21 665 (1968), and which has the following structuralformula: ##STR3##

Other 2-iminoimidazolidine compounds are listed in the chemicalliterature which are interesting from the viewpoint of potentiallyuseful pharmacodynamic properties. Such listed compounds include2-imino-1,3-diphenylimidazolidine and1-(p-chlorophenyl)-3-dodecyl-2-iminoimidazolidine.

One compound, 2-imino-1-methyl-3-phenylimidazolidine hydrochloride, hasthe following structure: ##STR4## This compound was screened forhypotensive and anti-arrhythmic and other pharmacodynamic activities.The said 2-iminoimidazolidine compound exhibited antiarrhythmicactivity, but was inactive with respect to hypoglycemic andanti-inflammatory properties. Further, the compound exhibitedhypertensive rather than hypotensive activity.

Accordingly, it is an object of this invention to provide a novel classof 2-iminoimidazolidine derivatives characterized by one or morepharmacological properties which qualify the said derivatives asprospective active agents in diverse pharmaceutical preparations for thetreatment of cardiovascular hypertension, cardiac arrhythmia and/orhyperglycemia, and related conditions which are responsive to the2-iminoimidazolidine active agents.

Other objects and advantages shall become apparent from the accompanyingdescription and examples.

DESCRIPTION OF THE INVENTION

One or more objects of the present invention are accomplished by theprovision of a novel class of pharmacologically active 4-substituted2-iminoimidazolidine derivatives. Illustrative of the novel class oforganic derivatives is a 2-iminoimidazolidine compound corresponding tothe formula: ##STR5## wherein R is alkyl; R¹ is a member selected fromhydrogen, alkyl, aryl, alkylaryl and haloaryl; R² is a member selectedfrom alkyl, aryl, alkylaryl, and haloaryl; X is a member selected fromamino, alkylamino, aralkylamino, cycloamino, and halogen; and n is theinteger 1 or 2.

The present invention also contemplates the pharmaceutically acceptableacid addition salts of the novel class of 4-substituted2-iminoimidazolidine derivatives. Such salts have improved watersolubility over the free bases. Typical acid addition salts are thosederived from mineral acids such as hydrochloric, hydrobromic, sulfuricand phosphoric; and organic acids such as acetic, citric, lactic,maleic, oxalic, fumaric and tartaric. The preferred acid addition saltis the hydrochloride. The acid addition salts are conveniently preparedby reaction of the basic compounds with the selected acid, either orboth of which may be in the form of ether, alcohol or acetone solutions.

The above described novel class of 4-substituted-2-iminoimidazolidinecompounds, and particularly the acid addition salt derivatives thereof,are characterized by significant pharmacological activity, which isindicative of their application in counteracting certain physiologicalabnormalities in humans. The 4-substituted 2-iminoimidazolidinecompounds possess varying degrees of hypotensive, nasal decongestant,antiarrhythmic, antisecretory, hypoglycemic (glucose tolerance),hypoglycemic (sugar cataract) and/or anti-inflammatory (pleuraleffusion) pharmacological activities.

In the above represented structural formula, the alkyl moiety in R, R¹,R² and X preferably is a lower alkyl radical containing between 1 andabout 4 carbon atoms, e.g., methyl, ethyl, propyol, isopropyl, butyl andisobutyl.

The aryl moiety in R¹, R² and X as designated in the structural formulapreferably is selected from phenyl and naphthyl radicals. Illustrativeof alkylaryl substituents are mono- and di-substituted phenyl andnaphthyl radicals such as tolyl, methylnaphthyl, dimethylphenyl,dimethylnaphthyl, propylphenyl, butylnaphthyl, and the like.Illustrative of aralkyl substituents are benzyl, phenethyl, phenpropyl,phenbutyl, naphthylmethyl, naphthylethyl, naphthylbutyl, and the like.The haloaryl substituent is preferably limited to fluoro, chloro, bromoor iodocontaining phenyl and naphthyl radicals.

Any of the aromatic nuclei enumerated above can contain, in addition tothose mentioned, other radical substituents which are not reactive orotherwise interfering under the conditions of compound preparation. Suchsubstituents include lower alkoxyl, trifluoromethyl, acetyl, and thelike.

The alkylamino substituent designated in the structural formulapreferably is a dialkylamino radical such as dimethylamino ordibutylamino. The aralkylamino substituent designated in the structuralformula preferably is a di(aralkyl)amino radical, and most preferably isa di(phenylalkyl)amino radical such as dibenzylamino,di(phenethyl)amino, di(phenbutyl)amino, and the like.

The halogen substituted designated for X in the structural formula canbe any of fluorine, chlorine, bromine and iodine, but preferably is achloro radical.

The cycloamino substituent designated for X in the structural formulapreferably is a five or six membered cycloaliphatic nucleus which caninclude other heteroatoms in addition to the amino nitrogen atom.Illustrative of cycloamines are pyrrolidino, alkylpyrrolidino,arylpyrrolidino, imidazolidino and substituted imidazolidino,piperidino, alkylpiperidino, arylpiperidino, morpholino,alkylmorpholino, arylmorpholino, piperazino, alkylpiperazino,arylpiperazino, 1,2,3,4-tetrahydroisoquinolyl,1,2,5,6-tetrahydropyridino, 4-(2-pyridyl)piperazino, phthalimido, andthe like.

With further reference to the aryl, alkylaryl and haloaryl substituentsdesignated in the structural formula, the preferred substituents arehydrocarbon radicals containing a total between 6 and about 12 carbonatoms, respectively.

The preferred aralkylamino substituent is a di(arylkyl)amino radical inwhich each aralkyl group contains between 7 and about 10 carbon atoms.The preferred cycloamino substituent is a 1-cycloamino radicalcontaining between 4 and about 12 carbon atoms.

Illustrative of specific 4-substituted 2-iminoimidazolidine compounds inaccordance with the present invention are4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine;1-ethyl-2-imino-4-(2-dimethylaminoethyl)-3-phenylimidazolidine;1-ethyl-2-imino-4-[2-(1-morpholino)ethyl]-3-phenylimidazolidine;4-(2-chloroethyl)-3-(p-chlorophenyl)-1-ethyl-2-iminoimidazolidine;3-(p-chlorophenyl)-1-ethyl-2-imino-4-(2-dimethylaminoethyl)imidazolidine;4-(2-chloroethyl)-1-ethyl-2-imino-3-(2,6-dimethylphenyl)imidazolidine;4-(2-chloroethyl)-3-(3-chloro-4-methylphenyl-1-ethyl-2-iminoimidazolidine;1-ethyl-2-imino-3-phenyl-4-[2-(1-piperidino)ethyl]imidazolidine;4-(2-dibenzylaminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine;4-(2-aminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine;1-ethyl-4-[2-(3-ene-4-phenyl-1-piperidino)ethyl]-2-imino-3-phenylimidazolidine;4-chloromethyl-2-imino-1-isopropyl-3-phenylimidazolidine;1-ethyl-2-imino-4-]2-(4-methyl-1-piperazino)ethyl]-3-phenylimidazolidine;4-(2-chloroethyl)-1-methyl-2-(methylamino-3-phenylimidazolidine; 4-(2-chloroethyl)-1,3-dimethyl-2-(phenylamino)imidazolidine;4-(2-chloroethyl)-1-methyl-3-phenyl-2-(phenylimino)imidazolidine;4-(2-chloroethyl)-2-(2,6-dichlorophenylimino)-1,3-dimethylimidazolidine;4-(2-chloroethyl)-2-imino-1-methyl-3-phenylimidazolidine;2-imino-1,3-dimethyl-4-(2-dimethylaminoethyl)imidazoldine;4-(2-chloroethyl)-1-methyl-2-(2,6-dimethylphenylimino)-3-phenylimidazolidine;2-imino-1-methyl-4-(2-dimethylaminoethyl)-3-phenylimidazolidine;4-(2-chloroethyl)-2-isopropyl imino)-1,3-dimethylimidazolidine;1-ethyl-4-[2-(4-hydroxy-4-phenyl-1-piperidino)ethyl]2-imino-3-phenylimidazolidine;3-(3-chloro-4-methylphenyl)-1-ethyl-2-imino-4-(2-dimethylaminoethyl)imidazolidine;and pharmaceutically acceptable acid addition salts thereof.

Preparation of 4-Substituted 2-Iminoimidazolidines

The invention 2-iminoimidazolidine compounds are readily prepared byconversion of suitable 2-imidazolidinone intermediates. A typicalsynthesis is illustrated by the following reaction scheme: ##STR6##wherein R, R¹, R² and n are as previously defined, and the halogen ispreferably a chloro radical.

A further transformation of the 2-iminoimidazolidine product illustratedabove is accomplished by interaction of the product with ammonia or aselected organic amine compound: ##STR7## wherein R, R¹, R² and n are aspreviously defined, and X¹ is one of amino, alkylamino, aralkylamino andcycloamino radicals.

The preparation of a 2-imidazolidinone starting material is illustratedby the following diagram with specific reference to the preparation of4-(chloroethyl)-1-methyl-2-oxo-3-phenylimidazolidine (I): ##STR8##

The preparation of 2-imidazolidinone derivatives in accordance with theabove illustrated reaction scheme is described in detail in U.S. Pat.No. 3,337,580 incorporated herein by reference.

Formulation of Pharmaceutical Compositions

In one embodiment, this invention provides a pharmaceutical compositionfor the treatment of cardiovascular hypertension comprising apharmaceutical carrier and a hypertension inhibiting quantity of a2-iminoimidazolidine compound corresponding to the formula: ##STR9##wherein R is alkyl; R¹ is a member selected from hydrogen, alkyl,phenyl, alkylphenyl, and chlorophenyl; R² is a member selected fromalkyl, phenyl, alkylphenyl, and chlorophenyl; X is a member selectedfrom amino, dialkylamino, di(phenylalkyl)amino, 1-piperidino,1-piperazino, 1-morpholino, and chloro; and n is the integer 1 or 2.

Illustrative of 2-iminoimidazolidine compounds suitable for functioningas a hypertension inhibiting agent in the pharmaceutical compositiondescribed above are the pharmaceutically acceptable acid addition saltsof 1-ethyl-2-imino-4-(2-dimethylaminoethyl)-3-phenylimidazolidine;3-(4-chlorophenyl)-1-ethyl-2-imino-4-(2-dimethylaminoethyl)imidazolidine; 1-ethyl-2-imino-3-phenyl-4-[2-(1-piperidino)ethyl]imidazolidine;4-[2-(dibenzylamino)ethyl]-1-ethyl-2-imino-3-phenylimidazolidine;4-(2-aminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine;4-[2-(3-ene-4-phenyl-1-piperidino)ethyl]-1-ethyl-2-imino-3-phenylimidazolidine;1-ethyl-2-imino-4-[2-(4-methyl-1-piperazino)-ethyl]-3-phenylimidazolidine;4-chloromethyl-2-imino-1-isopropyl-3-phenylimidazolidine;4-(2-chloroethyl)-1-methyl-2-methylimino-3-phenylimidazolidine; and thelike.

In another embodiment, this invention provides a pharmaceuticalcomposition for the treatment of hyperglycemia comprising apharmaceutical carrier and a hyperglycemia inhibiting quantity of a2-iminoimidazolidine compound corresponding to the formula: ##STR10##wherein R is alkyl; R¹ is a member selected from hydrogen, alkyl,phenyl, alkylphenyl, and chlorophenyl; R² is a member selected fromalkyl, phenyl, alkylphenyl, and chlorophenyl; X is a member selectedfrom amino, dialkylamino, di(phenylalkyl)amino, 1-piperidino,1-piperazino, 1-morpholino, and chloro; and n is the integer 1 or 2.

Illustrative of 2-iminoimidazolidine compounds suitable as ahyperglycemia inhibiting agent in the pharmaceutical compositiondescribed above are the pharmaceutically acceptable acid addition saltsof4-(2-chloroethyl)-1-ethyl-2-imino-3-(2,6-dimethylphenyl)imidazolidine;4-(2-chloroethyl)-1-methyl-2-methylimino-3-phenylimidazolidine;4-(2-chloroethyl)-1-methyl-2-phenylimino-3-phenylimidazolidine; and thelike.

In another embodiment, this invention provides a pharmaceuticalcomposition for the treatment of cardiac arrhythmia comprising apharmaceutical carrier and a cardiac arrhythmia inhibiting quantity of a2-iminoimidazolidine compound corresponding to the formula: ##STR11##wherein R is alkyl; R¹ is a member selected from hydrogen, alkyl,phenyl, alkylphenyl, and chlorophenyl; R² is a member selected fromalkyl, phenyl, alkylphenyl, and chlorophenyl; X is a member selectedfrom amino, dialkylamino, di(phenylalkyl)amino, 1-piperidino,1-piperazino, 1-morpholino, and chloro; and n is the integer 1 or 2.

Illustrative of 2-iminoimidazolidine compounds suitable as a cardiacarrhythmia inhibiting agent in the pharmaceutical composition describedabove are the pharmaceutically acceptable acid addition salts of4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine;4-(2-chloroethyl)-3-(4-chlorophenyl)-1-ethyl-2-iminoimidazolidine;4-(2-chloroethyl)-1-ethyl-2-imino-3-(2,6-dimethylphenyl) imidazolidine;4-(2-chloroethyl)-3-(3-chloro-4-methylphenyl)-1-ethyl-2-iminoimidazolidine;4-(2-chloroethyl)-1,3-dimethyl-2-phenyliminoimidazolidine; and the like.

In a further embodiment, this invention provides a pharmaceuticalcomposition for the treatment of sugar cataracts comprising apharmaceutical carrier and a sugar cataract formation inhibitingquantity of a 2-iminoimidazolidine compound corresponding to theformula: ##STR12## wherein R is alkyl; R¹ is a member selected fromhydrogen, alkyl, phenyl, alkylphenyl, and chlorophenyl; R² is a memberselected from alkyl, phenyl, alkylphenyl, and chlorophenyl; X is amember selected from amino, dialkylamino, di(phenylalkyl)amino,1-piperidino, 1-piperazino, 1-morpholino, and chloro; and n is theinteger 1 or 2.

Illustrative of 2-iminoimidazolidine compounds suitable as ahyperglycemic sugar cataract formation inhibiting agent in thepharmaceutical composition described above are the pharmaceuticallyacceptable acid addition salts of4-(2-chloroethyl)-1-ethyl-2-imino-3-(2,6-dimethylphenyl) imidazolidino;4-(2-chloroethyl)-1-methyl-2-methylimino-3-phenylimidazolidine;4-(2-chloroethyl-1,3-dimethyl-2-phenyliminoimidazolidine;4-(2-chloroethyl)-1-methyl-3-phenyl-2-phenyliminoimidazolidine;4-(2-chloroethyl)-2-(2,6-dichlorophenyl)imino-1,3-dimethylimidazolidine;4-(2-chloroethyl)-2-imino-1-methyl-3-phenylimidazolidine, and the like.

The pharmaceutical compositions of the present invention are prepared ina form suitable for administering to a living animal.

Pharmaceutical compositions for oral administration are preferablysolids and can take the form of capsules, tablets or coated tabletscontaining carriers conveniently used in the pharmaceutical art.Suitable tableting excipients include lactose, potato and maizestarches, talc, gelatin and stearic and silicic acids, magnesiumstearate, and polyvinyl pyrrolidone.

For parenteral administration the carrier or excipient can be a sterileparenterally acceptable liquid (e.g., water), or a parenterallyacceptable oil (e.g., arachis oil), contained in ampoules.

In compositions for rectal administration the carrier can comprise asuppository base such as cocoa butter or a glyceride.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of preferred dosage unit forms according to the invention. Eachdosage unit adapted for oral administration may conveniently contain 10to 40 mg. of the active ingredient; each dosage unit adapted forintracardial or intravenous administration may conveniently contain 1 to2 mg. per cc of the active ingredient; whereas each dosage unit adaptedfor intramuscular administration may conveniently contain 5 to 10 mg percc of the active ingredient.

Examples of compositions within the preferred ranges given are asfollows:

    ______________________________________                                        Capsules                                                                      Ingredients       Per Cap.                                                    ______________________________________                                        1.      Active ingredient                                                                            10.00 mg                                               2.      Lactose       146.00 mg                                               3.      Magnesium stearate                                                                           4.000 mg                                               ______________________________________                                    

Procedure

1. Blend 1, 2 and 3.

2. Mill this blend and blend again.

3. This milled blend is then filled into No. 1 hard gelatin capsules.

    ______________________________________                                        Tablets                                                                       Ingredients       Mg/Tab.                                                     ______________________________________                                        1.      Active ingredient                                                                           10.0 mg                                                 2.      Corn starch   20.0 mg                                                 3.      Kelacid       20.0 mg                                                 4.      Keltose       20.0 mg                                                 5.      Magnesium stearate                                                                           1.3 mg                                                 ______________________________________                                    

Procedure

1. Blend 1, 2, 3 and 4.

2. Add sufficient water portionwise to the blend from step 1 withcareful stirring after each addition. Such additions of water andstirring continue until the mass is of a consistency to permit itsconversion to wet granules.

3. The wet mass is converted to granules by passing it through theoscillating granulator, using 8-mesh screen.

4. The wet granules are then dried in an oven at 140° F.

5. The dried granules are then passed through an oscillating granulator,using a 10-mesh screen.

6. Lubricate the dry granules with 0.5% magnesium stearate.

7. The lubricated granules are compressed on a suitable tablet press.

    ______________________________________                                        Intravenous Injection                                                         Ingredients              Per ml                                               ______________________________________                                        1.      Active ingredient        1.0 mg                                       2.      pH 4.0 Buffer solution                                                                       q.s. to   1.0 ml                                       ______________________________________                                    

Procedure

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step 1.

3. The sterile solution is now aseptically filled into sterile ampoules.

4. The ampoules are sealed under aseptic conditions.

    ______________________________________                                        Intramuscular Injection                                                       Ingredients              Per ml                                               ______________________________________                                        1.      Active ingredient        5.0 mg                                       2.      Isotonic buffer                                                                              q.s. to   1.0 ml                                               solution 4.0                                                          ______________________________________                                    

Procedure

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step 1.

3. The sterile solution is now aseptically filled into sterile ampoules.

4. The ampoules are sealed under aseptic conditions.

    ______________________________________                                        Suppositories                                                                 Ingredients          Per Supp.                                                ______________________________________                                        1.      Active ingredient                                                                               10.0 mg                                             2.      Polyethylene Glycol 1000                                                                       1350.0 mg                                            3.      Polyethylene Glycol 4000                                                                        450.0 mg                                            ______________________________________                                    

Procedure

1. Melt 2 and 3 together and stir until uniform.

2. Dissolve No. 1 in the molten mass from step 1 and stir until uniform.

3. Pour the molten mass from step 2 into suppository molds and chill.

4. Remove the suppositories from molds and wrap.

The following examples are further illustrative of the presentinvention. The reactants and other specific ingredients are presented asbeing typical, and various modifications can be devised in view of theforegoing disclosure within the scope of the invention.

PREPARATION A

This example illustrates the preparation of3-anilino-1-methylpyrrolidine starting material. ##STR13##

A dry toluene (1 liter) suspension of sodamide (2 moles) was placed in a3-liter, 3-necked, round-bottomed flask equipped with a stirrer, refluxcondenser, thermometer and dropping funnel. While maintaining thedispersion at a temperature of 15°-40° C., 1-methyl-3-pyrrolidinol (2moles) was added dropwise. On completing the addition of thepyrrolidinol, the reaction mixture was stirred for two hours, graduallylowering the temperature to 10° C. A dry toluene (1 liter) solution ofp-toluenesulfonyl chloride (2 moles) was added dropwise maintaining thetemperature at less than 20° C. The reaction mixture was stirred for twohours at 20°-30° C. and then washed with cold water (2×500 ml). Thetoluene extract was dried over anhydrous calcium sulfate (Drierite).After removal of the drying agent, the toluene was removed byevaporation and the concentrated tosylate was allowed to react withaniline (4.4 moles, 10% excess). Reaction of the aniline with thetosylate [(1-methyl-3-pyrrolidyl)-p-toluenesulfonate] was effected byheating at 150° C. for two hours and then raising the temperature toreflux and heating for an additional three hours. The excess unreactedaniline was removed under reduced pressure (water aspirator vacuum) andthe remaining residue treated with a sufficient amount of cold dilutehydrochloric acid to effect solution. The acid solution was extractedseveral times with ethyl ether, cooled, and made basic with 50% aqueoussodium hydroxide. The free base was removed by extraction with ether.The other extracts were washed with water and dried over Drierite(anhydrous calcium sulfate). The drying agent was removed by filtrationand the ether removed under reduced pressure. The resultant residue wasthen distilled at reduced pressure. B.P. 124°-126° C. at 4 mm pressure.The product was obtained in 52% yield. The corresponding fumarate saltwas obtained from dry isopropanol solvent; m.p. 143°-144° C.

Analysis: Calculated for C₁₅ H₂₀ N₂ O₄ : C,61.63; H,6.90; N,9.58; Found:C,61.58; H,7.07; N,9.47.

PREPARATION B

This example illustrates the preparation of4-(2-chloroethyl)-1-methyl-2-oxo-3-phenylimidazolidine startingmaterial. ##STR14##

A solution of phosgene (0.88 mole) in chloroform (500 ml) was placed ina two-liter three-necked round-bottomed flask fitted with a stirrer,condenser, dropping funnel and thermometer, and cooled to zero° C. Whilestirring and maintaining the temperature at 10°-15° C.,3-anilino-1-methylpyrrolidine (0.44 mole) was added drop-wise. Oncompleting the addition of the substituted pyrrolidine, stirring wascontinued for two hours while the temperature rose to 25°-30° C. Thetemperature of the reaction mixture was then raised to reflux for aperiod of twelve hours. The reaction mixture was cooled to 0.5° C., andwashed with hydrochloric acid (6 N, 200 ml). The chloroform layer wasallowed to separate and then washed several times with water. Thechloroform extracts were dried over anhydrous sodium sulfate, filtered,and the chloroform evaporated on a rotary steam evaporator undermoderate reduced pressure. The isolated residue was purified by vacuumdistillation under reduced pressure. The 2-imidazolidinone derivativeexhibited a boiling range of 186°-190° C. at 0.1 mm Hg pressure(recrystallized from isopropyl ether; melting point 51°-52° C.) and wasobtained in 86% yield based on the starting pyrrolidine.

Analysis: Calculated for C₁₂ H₁₅ ClN₂ O: C,60.37; H,6.33; N,11.74;Cl,14.85; Found: C,60.40; H,6.44; N,11.71; Cl,14.76.

PREPARATION C

This example illustrates the preparation of3-(2,6-dimethylanilino-1-ethyl-pyrrolidine starting material. ##STR15##

To 125 ml. of 2,6-dimethylaniline was added 60 g. (0.34 mole) of3-bromo-1-ethylpyrrolidine and the resulting solution brought to refluxfor 18 hours. The solution was then partitioned between chloroform anddilute sodium hydroxide. The chloroform layer was dried over Na₂ SO₄,concentrated and distilled to yield 22 g. (29%) of product exhibiting aboiling range of 120°-130° C. at 0.2 mm Hg pressure.

PREPARATION D

This example illustrates the preparation of4-(2-chloroethyl)-1-ethyl-3-(2,6-dimethylphenyl)-2-oxoimidazolidinestarting material. ##STR16##

A solution of 10.9 g. (0.11 mole) of phosgene in 100 ml of chloroformwas placed in an ice bath and 21 g. (0.096 mole) of3-(2,6-dimethylanilino)-1-ethylpyrrolidine was added dropwise withstirring to the solution. The resulting solution was brought to refluxfor 2.5 hours, allowed to cool, and placed in an ice bath. To thissolution was added 10 g (0.1 mole) of triethylamine and the mixture wasstirred at room temperature for 0.5 hour. The chloroform layer wasextracted with dilute HCl followed by dilute NaOH. The chloroformextract was dried over Na₂ SO₄, concentrated and distilled to yield 19.2g (72%) of product exhibiting a boiling range of 175°-180° C. at 0.1 mmHg pressure.

EXAMPLE 1 Preparation of4-(2-Chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine Hydrochloride##STR17##

To 250 ml of phosphorus oxychloride was added 95.6 g (0.378 mole) of4-(2-chloroethyl-1-ethyl-2-oxo-3-phenyl imidazolidine and the mixturestirred at 70°-100° C. for 3.5 hours and concentrated on the rotaryevaporator, yielding an oil. The oil was added to approximately 500 mlof liquid ammonia and stirred while the ammonia was allowed toevaporate. The residue was partitioned between chloroform and diluteNaOH. The chloroform layer was concentrated and the residue dissolved inisopropyl ether. The isopropyl ether was treated with carbon black andfiltered. The ether was made acidic with ethereal HCl and the resultingprecipitate was collected by decanting the ether. The residue wascrystallized from isopropyl alcohol and isopropyl ether. Yield 61 g(56%); m.p. 175°-177° C. Analytical sample recrystallized from isopropylalcohol and isopropyl ether; m.p. 176°-177.5° C.

Analysis: Calculated for C₁₃ H₁₉ N₃ Cl₂ : C,54.17; H,6.64; N,14.57;Found: C,54.34; H,6.72; N,14.52.

EXAMPLE 2 Preparation of1-Ethyl-2-amino-4-(2-dimethylaminoethyl)-3-phenylimidazolidineDihydrochloride ##STR18##

To a 9.4 g (0.21 mole) of dimethylamine in 200 ml ethanol was added 20 g(0.0695 mole) of 4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidinehydrochloride and the solution heated to 100° C. in a steel bomb for 18hours. The contents were concentrated on the rotary evaporator and theresulting residue partitioned between chloroform and dilute NaOH. Thechloroform solution was concentrated and the residue dissolved inisobutyl methyl ketone which was acidified with ethereal HCl. Theresulting crystals were recrystallized from isopropanol-isobutyl methylketone. Yield 7.8 g (37.8%); m.p. 252°-254° C.

Analysis: Calculated for C₁₅ H₂₆ N₄ Cl₂ : C,54.05; H,7.86; N,16.81;Found: C,54.04; H,7.93; N,16.76.

EXAMPLE 3 Preparation of4-(2-Chloroethyl)-3-(p-chlorophenyl)-1-ethyl-2-iminoimidazolidineHydrochloride ##STR19##

A solution of 15.0 g (0.09 mole) of4-(2-chloroethyl)-3-(p-chlorophenyl)-1-ethyl-2-oxo-imidazolidine in 50ml of phosphorus oxychloride was refluxed 3.5 hour and concentrated invacuo. The residue was added dropwise into 100 ml of stirring liquidammonia. The ammonia was allowed to evaporate overnight. The residue waspartitioned between 150 ml of ethyl acetate and 150 ml of a 10% solutionof NaOH. The acetate layer was dried over Na₂ SO₄ and filtered. EtherealHCl was added until the solution had precipitated the salt and testedacidic to litmus paper. The salt was recrystallized from ethyl acetatewith a few drops of isopropanol added. The solid weighed 11.5 g (40%yield); m.p. 169°-170° C.

Analysis: Calculated for C₁₃ H₁₈ Cl₃ N₃ : C,48.39; H,5.62; N,13.02;Found: C,48.19; H,5.72; N,12.83.

EXAMPLE 4 Preparation of3-(4-Chlorophenyl)-1-ethyl-2-imino-4-(2-dimethyliminoethyl)imidazolidineDioxalate ##STR20##

A solution of 23.0 g (0.08 mole) of4-(2-chloroethyl)-3-(4-chlorophenyl)-1-ethyl-2-iminoimidazolidinehydrochloride in 200 ml of ethanol and 10.8 g (0.24 mole) ofdimethylamine was heated in a steel bomb at 100° C. for 18 hours. Thesolution was concentrated and the residue was partitioned between a 10%solution of NaOH and chloroform. The chloroform layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was dissolved inethanol and 7.2 g (0.08 mole) of oxalic acid was added. The resultingdioxalate salt was recrystallized from boiling ethanol with a few dropsof water added. The solid weighed 19.0 g (81% yield); m.p. 168°-171° C.

Analysis: Calculated for C₁₉ H₂₇ ClN₄ O₈ : C,48.06; H,5.73; N,11.80;Found: C,48.26; H,5.90; N,11.63.

EXAMPLE 5 Preparation of4-(2-Chloroethyl))-1-ethyl-3-(2,6-dimethylphenyl)-2-imidazolidineimineHydrochloride ##STR21##

A solution of 28 g. (0.1 mole) of4-(2-chloroethyl)-1-ethyl-3-(2,6-dimethylphenyl)-2-imidazolidinone in150 ml of phosphorous oxychloride was refluxed 18 hours and concentratedin vacuo on the steam bath. The residue was dissolved in 30 ml ofmethylene chloride and added dropwise to 200 ml of boiling ammonia. Theammonia was allowed to evaporate and the residue was partitioned betweenchloroform and aqueous potassium carbonate. The chloroform solution wasconcentrated and the residue dissolved in isobutyl methyl ketone. Thesolution was acidified with ethereal hydrogen chloride and the resultingoil was stirred until it crystallized. The crystals were recrystallizedtwice by dissolving them in about 90% isobutyl methyl ketone-10%isopropyl alcohol and boiling until the solution becomes cloudy(addition of isobutyl methyl ketone may be necessary) and allowing thisto cool. Yield 7.5 g (27%), m.p. 210°-212° C.

Analysis: Calculated for C₁₅ H₂₃ N₃ Cl₂ : C,56.96; H,7.33; N,13.29;Found: C,57.28; H,7.50; N,13.25.

EXAMPLE 6 Preparation of4-(2-Chloroethyl)-3-(3-chloro-4-methyl-phenyl)-1-ethyl-2-iminoimidazolidineHydrochloride ##STR22##

A solution of 30.0 g (0.10 mole) of4-(2-chloroethyl)-3-(3-chloro-4-methylphenyl)-1-ethyl-2-oxoimidazolidinein 175 ml of phosphorus oxychloride was refluxed 56 hours. The solutionwas concentrated in vacuo, and the residue was added dropwise intostirring liquid ammonia. The ammonia was allowed to evaporate. Theresidue was partitioned between 150 ml of a 10% solution of hydrochloricacid and 150 ml of chloroform. The acid solution was made basic tolitmus paper with a 10% solution of sodium hydroxide, and was extractedwith an equal amount of chloroform. The solution was dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was dissolvedin ethyl acetate and a hydrochloride salt was made by the addition ofethereal HCl until the mixture was acid to litmus paper. The salt wasrecrystallized in ethyl acetate. The off-white solid weighed 7.0 g (21%yield); m.p. 225°-226° C.

Analysis: Calculated for C₁₄ H₂₀ Cl₃ N₃ : C,49.94; H,5.99; N,12.48;Found: C,49.77; H,5.90; N,12.31.

EXAMPLE 7 Preparation of1-Ethyl-2-imino-3-phenyl-4-[2-(1-piperidino)ethyl]imidazolidineDihydrochloride ##STR23##

With piperidine as the solvent, a solution of 20.0 g (0.069 mole) of4-(2-chloroethyl)-1-ethyl-2-imino-3-phenyl imidazolidine hydrochloridewas refluxed for 2 hours and concentrated. The residue was partitionedbetween chloroform and a potassium carbonate solution. The chloroformlayer was dried (Na₂ SO₄), filtered and concentrated. The residue wasdissolve in methyl isobutyl ketone, and ethereal HCl was added to form asalt. It was crystallized twice from ethanol, and weighed 13.5 g (58%yield) m.p. 270° C. (dec.).

Analysis: Calculated for C₁₈ H₃₀ Cl₂ N₄ : C,57.91; H,8.10; N,15.01;Found: C,57.45; H,8.08; N,14.88.

EXAMPLE 8 Preparation of4-(2-Dibenzylaminoethyl)-1-ethyl-2-imino-3-phenylimidazolidineHydrochloride Monohydrate ##STR24##

With dibenzylamine as the solvent, 28.7 g (0.10 mole) of4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine hydrochloridewas refluxed for 2 hours and concentrated in vacuo. After partitioningbetween a dilute potassium carbonate solution and chloroform, thechloroform layer was dried (Na₂ SO₄), filtered, and concentrated invacuo. After dissolving the residue in a 50% mixture of methyl isobutylketone and isooctane, a salt was formed with ethereal HCl. The salt wasrecrystallized twice from a 50% solution of ethyl acetate andisopropanol, and weighed 4.18 g (30% yield); m.p. 207°-208° C.

Analysis: Calculated for C₂₇ H₃₆ Cl₂ N₄ O: C,64.41; H,7.21; N,11.13;Found: C,64.72; H,7.04; N,11.03.

EXAMPLE 9 Preparation of4-(2-Aminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine Dihydrochloride##STR25##

A solution of 10.0 g (0.023 mole) of4-(2-dibenzylaminoethyl)-1-ethyl-2-imino-3-phenylimidazolidinedihydrochloride hydrate in 175 ml of ethanol was shaken for 7 hours in aParr apparatus at 70° C. with palladium catalyst at 45 p.s.i. hydrogen.After filtering and concentrating the filtrate in vacuo, the solidresidue was recrystallized from a 80/20% mixture of isopropanol-ethanol.The salt weighed 4.55 g (70% yield); m.p. 223°-224° C.

Analysis: Calculated for C₁₃ H₂₂ Cl₂ N₄ : C,51.15; H,7.27; N,18.35;Found: C,50.99; H,7.22; N,18.02.

EXAMPLE 10 Preparation of 4-[2-(3-Ene-4-phenyl-1-piperidino)ethyl]-1-ethyl-2-imino-3-phenylimidazolidine Dihydrochloride Monohydrate##STR26##

By partitioning between chloroform and a dilute sodium hydroxidesolution, 16.0 g (0.10 mole) of 1,2,5,6-tetrahydro-4-phenylpyridinehydrochloride was converted to the free base and dissolved in 125 ml ofdry toluene. To this 14.3 g (0.05 mole) of4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine hydrochloridewas added, and the solution was refluxed for 2 hours and concentrated invacuo. The residue was partitioned between a dilute hydrochloric acidsolution and ethyl acetate, and the acid layer was then made basic witha dilute potassium carbonate solution and extracted with ethyl acetate.Ethereal hydrogen chloride was added until a salt formed, which wasrecrystallized from a 50% solution of isopropyl alcohol and ethylacetate and weighed 5.4 g (24% yield); m.p. 236°-239° C. (dec).

Analysis: Calculated for C₂₄ H₃₄ Cl₂ N₄ O: C,62.93; H,7.36; N,12.04;Found: C,62.90; H,7.09; N,12.02.

EXAMPLE 11 Preparation of1-Ethyl-2-imino-4-[2-(4-methyl-1-piperazino)ethyl]-3-phenylimidazolidineTrihydrochloride Monohydrate ##STR27##

With methylpiperazine as the solvent, 14.5 g (0.05 mole) of4-(2-chloroethyl-1-ethyl-2-imino-3-phenylimidazolidine hydrochloride wasrefluxed for two hours. The solution was concentrated in vacuo, and theresidue was partitioned between chloroform and a dilute potassiumcarbonate solution. The chloroform layer was dried (Na₂ SO₄), filteredand concentrated in vacuo. The residue was dissolved in ethyl acetateand treated with ethereal HCl until acidic and a salt precipitated. Itwas recrystallized twice from a mixture of ethyl acetate andisopropanol, and weighed 4.0 g. (20% yield); m.p. 260°-262° C.

Analysis: Calculated for C₁₈ H₃₄ Cl₃ N₅ O: C,48.82; H,7.74; N,15.81;Found: C,49.07; H,7.53 N,15.46.

EXAMPLE 12 Preparation of4-(2-Chloroethyl)-1-methyl-2-(methylimino)-3-phenylimidazolidineFumarate ##STR28##

To 50 ml of POCl₃ was added 15 g (0.062 mole) of4-(2-chloroethyl)-1-methyl-2-oxo-3-phenylimidazolidine and the solutionrefluxed for 18 hours and concentrated. The residue was dissolved in 50ml of CH₂ Cl₂ and added dropwise with stirring and dry ice bath cooling(about -20° C.) to 50 ml of methylamine. The mixture was stirred about 2hours while the excess methylamine evaporated. The residue was extractedwith a saturated NaHCO₃ solution. The CH₂ Cl₂ solution was dried (Na₂SO₄) and concentrated. The resulting concentrate was distilled at about180° C./0.01 mm Hg. The distillate was treated with fumaric acid inisopropanol to yield the salt product; m.p. 133°-135° C.

Analysis: Calculated for C₁₇ H₂₂ ClN₃ O₄ : C,55.51; H,6.03; N,11.42;Found: C,55.91; H,6.13; N,11.42.

EXAMPLE 13 Preparation of4-(2-Chloroethyl)-1,3-dimethyl-2-phenyliminoimidazolidine Fumarate##STR29##

To 8.0 g (0.045 mole) of4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml ofphosphorus oxychloride, and the solution was refluxed for 18 hours, andconcentrated in vacuo. The residue was dissolved in 25 ml of methylenechloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring atroom temperature. Stirring was continued for two hours. The solution wasdiluted with chloroform and washed with dilute sodium hydroxidesolution. The chloroform was dried, filtered and concentrated in vacuo.The residue was dissolved in isopropyl alcohol and treated with 5.2 g.(0.045 mole) fumaric acid, and the resulting fumarate was recrystallizedfrom isopropyl alcohol and weighed 9.0 g (50% yield); m.p. 109°-112° C.

Analysis: Calculated for C₁₇ H₂₂ ClN₃ O₄ : C,55.51; H,6.03; N,11.42;Found: C,55.42; H,6.01; N,11.36.

EXAMPLE 14 Preparation of4-(2-Chloroethyl)-1-methyl-3-phenyl-2-phenyliminoimidazolidine Fumarate##STR30##

To 23.0 g (0.1 mole) of4-(2-chloroethyl)-1-methyl-2-oxo-3-phenylimidazolidine was added 150 mlof phosphorus oxychloride, and the solution was refluxed for 18 hours.After concentrating in vacuo, the residue was dissolved in 20 ml ofmethylene chloride and added dropwise to a stirring solution of 9.0 g(0.10 mole) of aniline in methylene chloride. The solution was stirredat room temperature for one hour and washed with a dilute 10% sodiumhydroxide. The methylene chloride layer was then dried, filtered, andconcentrated in vacuo. The residue was dissolved in isopropanol andtreated with 11.6 g. of fumaric acid, and the resulting salt wasrecrystallized twice from ethanol and weighed 12.0 g (28% yield); m.p.136°-137° C.

Analysis: Calculated for C₂₂ H₂₄ N₃ O₄ : C,61.47; H,5.63; N,9.77; Found:C,61.17; H,5.62; N,9.66.

EXAMPLE 15 Preparation of4-(2-Chloroethyl)-2-(2,6-dichlorophenylimino)-1,3-dimethylimidazolidineSesquifumarate ##STR31##

To 26.0 g (0.148 mole) of4-(2-chloroethyl)-1,3-dimethyl-2-oxoimidazolidine was added 125 ml. ofphosphorous oxychloride, and the solution was refluxed overnight. Afterconcentrating in vacuo, the residue was dissolved in methylene chloride,15.0 g of triethylamine was added, and this solution was dropped into24.0 g (0.148 mole) of 2,5-dichloroaniline, while stirring at roomtemperature. Stirring was continued for two hours. After washing with adilute potassium bicarbonate solution, the organic layer was dried,filtered and concentrated in vacuo. The residue was dissolved in 50%isopropyl ether-50% isopropyl alcohol. Hydrogen chloride was added,producing the hydrochloride salt of the excess dichloroaniline which wasremoved by filtration. The filtrate was concentrated in vacuo and theresidue partitioned between a dilute hydrochloric acid solution andethyl acetate. The acid layer was made basic with a dilute sodiumbicarbonate solution and extracted with chloroform, which was dried,filtered, and concentrated in vacuo. The residue was columned onFlorisil using 20 to 30% methanol in benzene to remove the product fromthe column. After concentrating the combined fractions in vacuo, theresidue was dissolved in isopropanol alcohol and treated with fumaricacid (1.5 g) and recrystallized from the same. Yield 2.0 g (3%); m.p.162°-164° C.

Analysis: Calculated for C₁₉ H₂₂ Cl₃ N₃ O₆ : C,46.13; H,4.48; N,8.49;Found: C,46.05; H,4.55; N,8.32.

EXAMPLE 16 Preparation of4-(2-Chloroethyl)-2-imino-1-methyl-3-phenylimidazolidine Hydrochloride##STR32##

To 23.8 g (0.10 mole) of4-(2-chloroethyl)-1-methyl-2-oxo-3-phenylimidazolidine was added 125 mlof phosphorus oxychloride, and the solution was refluxed overnight. Uponconcentrating in vacuo, the residue was dissolved in methylene chlorideand added dropwise to 150 ml of stirring liquid ammonia. After all theliquid had evaporated, the resulting residue was partitioned betweenice-cold potassium bicarbonate solution and chloroform. The organiclayer was dried, filtered and concentrated in vacuo. The residue wasdissolved in ethyl acetate and treated with ethereal hydrogen chloride.The salt was recrystallized from ethyl acetate-ethanol (3:1) and weighed9.34 g (34% yield); m.p. 220°-222° C.

Analysis: Calculated for C₁₂ H₁₇ Cl₂ N₃ : C,52.57; H,6.25; N,15.33;Found: C,52.34; H,6.29; N,15.23.

EXAMPLE 17 Preparation of 2-Imino-1,3-dimethyl-4-(2-dimethylaminoethyl)imidazolidine Dihydrochloride Hydrate (4:1) ##STR33##

To 10.0 g (0.047 mole) of4-(2-chloroethyl)-2-imino-1,3-dimethylimidazolidine hydrochloride wasadded 6.8 g (0.15 mole) of dimethylamine in 175 ml of methanol. Themixture was heated in a steel bomb at 100° C. for 15 hours. Afterconcentrating in vacuo, the residue was partitioned between a dilutesodium carbonate solution and chloroform. The organic layer was dried(Na₂ SO₄), filtered, and concentrated in vacuo. The residue wasdissolved in ethyl acetate and treated with ethereal HCl. Thehydrochloride was recrystallized from ethanol twice, and weighed 3.2 g(26% yield); m.p. 210°-212° C.

Analysis: Calculated for C₃₆ H₉₀ Cl₈ N₁₆ O: C,41.31; H,8.67; N,21.41;Found: C,41.49; H,8.80; N,21.51.

EXAMPLE 18 Preparation of 4-Chloromethyl-2-imino-1-isopropyl3-phenylimidazolidine Fumarate ##STR34##

A. To a stirring solution of 92.4 (1.10 mole) of sodium bicarbonate in250 ml of water was slowly added 100.0 g (0.35 mole) of1-isopropyl-3-azetidinylmethane sulfonate oxalate. To the above wasadded 250 ml of aniline and the solution was refluxed for three hours.After cooling, the solution was extracted with ethyl acetate, and theacetate layer was dried (Na₂ SO₄), filtered and concentrated in vacuo.The residue was distilled at 100°-110° C./0.1 mm Hg. Yield 38.8 g (58%).Five grams were dissolved in isopropyl alcohol and treated with etherealHCl. The resulting salt was recrystallized from ethanol. The yield of3-anilino-1-isopropyl-azetidine hydrochloride hemihydrate was 6 g.

B. To a stirring cooled solution of 17.2 g (0.176 mole) of phosgene in250 ml of chloroform was added dropwise, 30.0 g (0.16 mole) of3-anilino-1-isopropylazetidine. The solution was refluxed two hours, and19.4 g (0.19 mole) of triethylamine was added at room temperature.Stirring was continued for one hour. The chloroform was washed withdilute HCl and then with dilute NaOH solution. After drying with Na₂SO₄, filtering and concentrating in vacuo, the residue was distilled at172°-175° C./0.1 mm Hg. Yield 39.0 g (97%). Crystals formed uponstanding and were recrystalized from isopropyl ether. There was obtained21.5 g (53%) of 4-chloromethyl-1-isopropyl-2-one-3-phenylimidazolidineproduct; m.p. 61°-63° C.

C. A stirring solution of 16.0 g (0.063 mole) of4-chloromethyl-1-isopropyl-2-oxo-3-phenylimidazolidine in 200 ml ofphosphorus oxychloride was refluxed for three hours and concentrated invacuo. The residue was dissolved in 20 ml of methylene chloride and thesolution dropped into stirring liquid ammonia. The ammonia was allowedto evaporate. The residue was partitioned between dilute HCl andisopropyl ether. The acid layer was made basic with dilute sodiumcarbonate solution and was extracted with chloroform. The organic layerwas dried (Na₂ SO₄), filtered and concentrated in vacuo. The residuewhich weighed 7.0 g was treated with an equivalent of fumaric acid inisopropyl alcohol. The salt was recrystallized from ethanol. Therecovered 4-chloromethyl-2-imino-1-isopropyl-3-phenylimidazolidinefumarate product weighed 8.0 g (31% yield); m.p. 170°-171° C.

Analysis: Calculated for C₁₇ H₂₂ ClN₃ O₄ : C,55.51; H,6.03; N,11.42;Found: C,55.50; H,6.07; N,11.41.

What is claimed is:
 1. A 2-iminoimidazolidine compound corresponding tothe formula: ##STR35## wherein R is an alkyl radical containing between1 and 4 carbon atoms; R¹ is a member selected from hydrogen, an alkylradical containing between 1 and 4 carbon atoms, phenyl and phenylsubstituted with one or more members selected from halogen and an alkylradical containing between 1 and 4 carbon atoms; R² is a member selectedfrom an alkyl radical containing between 1 and 4 carbon atoms, phenyland phenyl substituted with one or more members selected from an alkylradical containing between 1 and 4 carbon atoms and halogen; X ishalogen; and n is the integer 1 or 2, or a pharmaceutically acceptableacid addition salt thereof.
 2. A 2-iminoimidazolidine compound inaccordance with claim 1 wherein R is an alkyl radical containing between1 and about 4 carbon atoms.
 3. A 2-iminoimidazolidine compound inaccordance with claim 1 wherein R is methyl.
 4. A 2-iminoimidazolidinecompound in accordance with claim 1 wherein R is ethyl.
 5. A2-iminoimidazolidine compound in accordance with claim 1 wherein R¹ ishydrogen.
 6. A 2-iminoimidazolidine compound in accordance with claim 1wherein R¹ is an alkyl radical containing between 1 and about 4 carbonatoms.
 7. A 2-iminoimidazolidine compound in accordance with claim 1wherein R¹ is methyl.
 8. A 2-iminoimidazolidine compound in accordancewith claim 1 wherein R¹ is phenyl or phenyl substituted with one or moremembers selected from halogen and an alkyl radical containing between 1and 4 carbon atoms.
 9. A 2-iminoimidazolidine compound in accordancewith claim 1 wherein R¹ is phenyl.
 10. A 2-iminoimidazolidine compoundin accordance with claim 1 wherein R¹ is dimethylphenyl.
 11. A2-iminoimidazolidine compound in accordance with claim 1 wherein R¹ isdichlorophenyl.
 12. A 2-iminoimidazolidine compound in accordance withclaim 1 wherein R² is an alkyl radical containing between 1 and about 4carbon atoms.
 13. A 2-iminoimidazolidine compound in accordance withclaim 1 wherein R² is methyl.
 14. A 2-iminoimidazolidine compound inaccordance with claim 1 wherein R² is phenyl or phenyl substituted withone or more members selected from halogen and an alkyl radicalcontaining between 1 and 4 carbon atoms.
 15. A 2-iminoimidazolidinecompound in accordance with claim 1 wherein R² is phenyl.
 16. A2-iminoimidazolidine compound in accordance with claim 1 wherein R² isdimethylphenyl.
 17. A 2-iminoimidazolidine compound in accordance withclaim 1 wherein R² is chlorophenyl.
 18. A 2-iminoimidazolidine compoundin accordance with claim 1 wherein R² is chloro-methylphenyl.
 19. A2-iminoimidazolidine compound in accordance with claim 1 wherein X ischloro.
 20. 4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine, ora pharmaceutically acceptable acid addition salt thereof. 21.4-(2-Chloroethyl)-3-(4-chlorophenyl)-1-ethyl-2-iminoimidazolidine, or apharmaceutically acceptable acid addition salt thereof. 22.4-(2-Chloroethyl)-1-ethyl-2-imino-3-(2,6-dimethylphenyl)imidazolidine,or a pharmaceutically acceptable acid addition salt thereof. 23.4-(2-Chloroethyl)-3-(3-chloro-4-methylphenyl)-1-ethyl-2-iminoimidazolidine,or a pharmaceutically acceptable acid addition salt thereof. 24.4-Chloromethyl-2-imino-1-isopropyl-3phenylimidazolidine, or apharmaceutically acceptable acid addition salt thereof. 25.4-(2-Chloroethyl)-1-methyl-2-(methylimino)-3-phenylimidazolidine, or apharmaceutically acceptable acid addition salt thereof. 26.4-(2-Chloroethyl)-1,3-dimethyl-2-phenyliminoimidazolidine, or apharmaceutically acceptable acid addition salt thereof. 27.4-(2-Chloroethyl-1-methyl-3-phenyl-2-phenyliminoimidazolidine, or apharmaceutically acceptable acid addition salt thereof. 28.4-(2-Chloroethyl)-2-(2,6-dichlorophenylimino)-1,3-dimethylimidazolidine,or a pharmaceutically acceptable acid addition salt thereof. 29.4-(2-Chloroethyl)-1-methyl-2-imino-3-phenylimidazolidine, or apharmaceutically acceptable acid addition salt thereof. 30.4-(2-Chloroethyl)-1-methyl-2-(2,6-dimethylphenylimino)-3-phenylimidazolidine,or a pharmaceutically acceptable acid addition salt thereof. 31.4-(2-Chloroethyl)-2-isopropylimino-1,3-dimethylimidazolidine, or apharmaceutically acceptable acid addition salt thereof.